CA2533492A1 - Use of 3,7-diazabicyclo[3,3,1]nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients - Google Patents
Use of 3,7-diazabicyclo[3,3,1]nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients Download PDFInfo
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- CA2533492A1 CA2533492A1 CA002533492A CA2533492A CA2533492A1 CA 2533492 A1 CA2533492 A1 CA 2533492A1 CA 002533492 A CA002533492 A CA 002533492A CA 2533492 A CA2533492 A CA 2533492A CA 2533492 A1 CA2533492 A1 CA 2533492A1
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- diazabicyclo
- carbon atoms
- nonane
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
The present invention relates to the use of 3,7-diazabicyclo[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7~diazabicyclo[3,3,1]nonane compounds, and most preferably to the use of tedisamil, and the physiologically acceptable acid addition salts and/or solvates thereof, for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
Description
USE OF 3,7-DIAZABICYCLO'3,3,1!NONANE COMPOUNDS FOR THE TREATMENT AND/OR
PROPHYLAXIS OF ARRHYTHMIC EVENTS IN MALE HUMAN PATIENTS
Description The present invention relates to a novel medicinal use of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably to a novel riiedicinal use of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds.
9,9-Alkylene-3,7-diazabicyclononane compounds of formula I and their pharmacological activities are known from published European Patent No. EP
103,833 and the corresponding U.S. Pat. No. 4,550,112, and Finnish Patent No. FI
76,338.
Compounds of formula I are a sub-group of the 9,9-N,N'-tetra-substituted 3,7-diaza-bicyclo[3.3.1]nonane compounds described in the aforementioned patent specifications and can be prepared by the methods described therein. The aforementioned patent specifications disclose that the compounds have useful cardio-active properties, particularly oxygen-saving effects and effects on the heart rate and heart rhythm in general, and are distinguished by a high physiological tolerance. Thus, the compounds show a satisfactory anti-arrhythmic action even at low doses. Moreover, the undesired negative effect on the contractile power of the heart is extremely low; i.e.
the compounds have a particularly favourable ratio of anti-arrhythmic or the refractory period of the heart prolonging activities, to negative inotropic secondary activities.
Moreover, it is described in Burow et al., U.S. Pat. No. 5,164,401, the compounds also have a pronounced diuretic effect with a favourable ratio between sodium and potassium excretion.
Furthermore special salts and their manufacture of the 3,7-diazabicyclo[3,3,1]-nonane compounds, in particular of 9,9-alkylene-3,7-diazabicyclo[3,3,1]nonane compounds are described in US 5,324,732. Thus, US 5,324,732 describes fumaric acid salts of said compounds containing 1.5 moles of fumaric acid per mole of the compound.
The document provides also a reference to some general pharmacological activities of the compounds of the formula I which are described in the published European Patent No. EP 103,833 and in the corresponding US Patent No. 4,550,112. The US Patent No.
4,912,113 also provides new 3,7-diazabicyclo[3,3,1]nonane compounds and their pharmacological properties, and intermediates. However, none of the cited patents addresses any distinction of efFects when administering tedisamil to different genders.
It is worthwhile to mention that the referenced prior art patent documents do not contain any clinical data related to human beings, however all the pharmacological evidence provided is limited to pre-clinical testing in animals like rats and dogs. In addition some of the pre-clinical results are also described in the scientific literature. For example Fischbach et al. describe "Tedisamil in a Chronic Canine Model of Atrial Flutter"
(Journal of Cardiovascular Pharmacology, vol. 34, no. 2, August 1999, p. 212 to 218), and also the "Conversion of Atrial Fibrillation by the Experimentasl Antiarrhythmic Drug Tedisamil in Two Canine Models" (Journal of Cardiovascular Electrophsiology, vol. 12, no. 10, October 2001, p. 1138 to 1144). However, Fischbach et al. do not address any distinction of effects when administering tedisamil to different genders. Opie et al.
discuss on ~Tedisamil in Coronory Disease: Additional Benefits in Therapy of Atrial Fibrillation?" (Journal of Cardiovascular Pharmacology and Therapeutics, vol.
8, no.
supplement 1, 2003, p. S 33 to S 37). They give data and figures studies done in the isolated coronary-ligated rat heart, and on the efFects of tedisamil on exercise-induced ischemia on diastolic and systolic segment length, and on myocardial oxygen consumption in exercising dogs. It is also stated that tedisamil has anti-ischemic properties, as studied in rat hearts, rabbits, running dogs, and humans;
however, Opie et al. do not address any distinction of effects when administering tedisamil to different genders.
Furthermore, Julius Papp et al. have described the "Effects of Bertosamil on Atrial and Ventricular Treshold for Fibrillo-Flutter in Comparison with Quinidine in Anaesthetized Cats" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992, p. 156 to 157), and the "EfFects of Bertosamil on Rabbit Atrial and Ventricular Transmembrane Potentials" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992, p. 139 to 140).
However, also Papp et al. do not address any distinction of effects when administering tedisamil to difFerent genders.
Although Nicholas A. Flores pertains to clinical phase studies in humans under the title "Tedisamil Solvay" in Current Opinion in Investigational Drugs, vol.
2, no. 1, 2001, p. 97 to 103), no distinction of the efFects of tedisamil on different genders is reported.
PROPHYLAXIS OF ARRHYTHMIC EVENTS IN MALE HUMAN PATIENTS
Description The present invention relates to a novel medicinal use of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably to a novel riiedicinal use of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds.
9,9-Alkylene-3,7-diazabicyclononane compounds of formula I and their pharmacological activities are known from published European Patent No. EP
103,833 and the corresponding U.S. Pat. No. 4,550,112, and Finnish Patent No. FI
76,338.
Compounds of formula I are a sub-group of the 9,9-N,N'-tetra-substituted 3,7-diaza-bicyclo[3.3.1]nonane compounds described in the aforementioned patent specifications and can be prepared by the methods described therein. The aforementioned patent specifications disclose that the compounds have useful cardio-active properties, particularly oxygen-saving effects and effects on the heart rate and heart rhythm in general, and are distinguished by a high physiological tolerance. Thus, the compounds show a satisfactory anti-arrhythmic action even at low doses. Moreover, the undesired negative effect on the contractile power of the heart is extremely low; i.e.
the compounds have a particularly favourable ratio of anti-arrhythmic or the refractory period of the heart prolonging activities, to negative inotropic secondary activities.
Moreover, it is described in Burow et al., U.S. Pat. No. 5,164,401, the compounds also have a pronounced diuretic effect with a favourable ratio between sodium and potassium excretion.
Furthermore special salts and their manufacture of the 3,7-diazabicyclo[3,3,1]-nonane compounds, in particular of 9,9-alkylene-3,7-diazabicyclo[3,3,1]nonane compounds are described in US 5,324,732. Thus, US 5,324,732 describes fumaric acid salts of said compounds containing 1.5 moles of fumaric acid per mole of the compound.
The document provides also a reference to some general pharmacological activities of the compounds of the formula I which are described in the published European Patent No. EP 103,833 and in the corresponding US Patent No. 4,550,112. The US Patent No.
4,912,113 also provides new 3,7-diazabicyclo[3,3,1]nonane compounds and their pharmacological properties, and intermediates. However, none of the cited patents addresses any distinction of efFects when administering tedisamil to different genders.
It is worthwhile to mention that the referenced prior art patent documents do not contain any clinical data related to human beings, however all the pharmacological evidence provided is limited to pre-clinical testing in animals like rats and dogs. In addition some of the pre-clinical results are also described in the scientific literature. For example Fischbach et al. describe "Tedisamil in a Chronic Canine Model of Atrial Flutter"
(Journal of Cardiovascular Pharmacology, vol. 34, no. 2, August 1999, p. 212 to 218), and also the "Conversion of Atrial Fibrillation by the Experimentasl Antiarrhythmic Drug Tedisamil in Two Canine Models" (Journal of Cardiovascular Electrophsiology, vol. 12, no. 10, October 2001, p. 1138 to 1144). However, Fischbach et al. do not address any distinction of effects when administering tedisamil to different genders. Opie et al.
discuss on ~Tedisamil in Coronory Disease: Additional Benefits in Therapy of Atrial Fibrillation?" (Journal of Cardiovascular Pharmacology and Therapeutics, vol.
8, no.
supplement 1, 2003, p. S 33 to S 37). They give data and figures studies done in the isolated coronary-ligated rat heart, and on the efFects of tedisamil on exercise-induced ischemia on diastolic and systolic segment length, and on myocardial oxygen consumption in exercising dogs. It is also stated that tedisamil has anti-ischemic properties, as studied in rat hearts, rabbits, running dogs, and humans;
however, Opie et al. do not address any distinction of effects when administering tedisamil to different genders.
Furthermore, Julius Papp et al. have described the "Effects of Bertosamil on Atrial and Ventricular Treshold for Fibrillo-Flutter in Comparison with Quinidine in Anaesthetized Cats" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992, p. 156 to 157), and the "EfFects of Bertosamil on Rabbit Atrial and Ventricular Transmembrane Potentials" (Pharmaclogical Research, vol. 25, no. supplement 2, 1992, p. 139 to 140).
However, also Papp et al. do not address any distinction of effects when administering tedisamil to difFerent genders.
Although Nicholas A. Flores pertains to clinical phase studies in humans under the title "Tedisamil Solvay" in Current Opinion in Investigational Drugs, vol.
2, no. 1, 2001, p. 97 to 103), no distinction of the efFects of tedisamil on different genders is reported.
It is the object of the invention to provide a novel medical use or a new method of treating male human patients in need of treatment and/or prophylaxis of anti-arrhythmic events.
Another object of the invention is to provide new anti-arrhythmic pharmaceutical compositions having an improved activity profile for the use in male human patients.
The objects of the invention are achieved by surprisingly discovering that 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds are particularly suitable for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients. According to a further aspect of the invention, the objects are achieved by providing an anti-arrhythmic pharmaceutical composition comprising an anti-arrhythmic amount effective in male human patients of at least one anti-arrhythmic active 3,7-diaza-bicyclo[3,3,1]nonane compound as described in the present invention.
The subject of the invention is therefore the use of the use of 3,7-diaza-bicyclo[3,3,1]nonane compounds, its physiologically acceptable acid addition salts and/or solvates thereof for the production of a pharmaceutical preparation for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
The compounds suitable for this novel medicinal use in male human patients are 3,7-diazabicyclo[3,3,1]nonane compounds corresponding to the Formula I:
I
R1 ~N N~R4 wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, or a benzyl group, R2 represents a lower alkyl group, and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms, and R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, a group corresponding to the Formula a:
/ /~ a z wherein R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and Z represents an alkylene chain containing from 1 to 3 carbon atoms or a propenylene chain having a double bond which is conjugated with the phenyl group, or a group corresponding to the Formula b:
\ R6 a CH
a R7 wherein R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy, or a physiologically acceptable acid addition salt andlor solvate thereof.
Particularly suited compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula I, wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms. In further preferred compounds of Formula I the substituent R4 represents an alkyl group containing from 1 to 6 carbon atoms, a cycloalkylalkyl group containing from 4 to 7 carbon atoms, or a group corresponding to Formula b.
Preferred compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula 1, wherein R1 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms, and R4 represents an alkyl group containing from 3 to fi carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms. Said 3,7-diazabicyclo-[3,3,1]nonane compound may be a 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compound of Formula I wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another each denote a straight-chain or branched alkyl group of 3-4 carbon atoms or the cyclopropylmethyl group, and physiologically acceptable acid addition salts andlor solvates thereof.
Preferred salts for this group of compounds are fumaric acid salts of 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compounds containing 1.5 moles of fumaric acid per mole of compound of formula I.
Further preferred compounds for the novel medicinal use in male human patients according to the invention are compounds selected from the group consisting of N,N'-dicyclopropyl-methyl-9, 9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane {tedisamil), N-isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3,1]nonane, and physiologically acceptable acid addition salts and/or solvates thereof.
Preferred salts for this group of compounds are fumaric acid salts of N,N'-dicyclopropylmethyl-9, tetramethylene-3,7-diazabicyclo[3,3,1]nonane (tedisamil) or of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo[3,3,1]nonane containing 1.5 moles of fumaric acid per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound.
Alternatively, as acid addition salts of the 3,7-diazabicyclo[3,3,1]nonane compounds the hydrochloride salts are also very suitable for the novel medicinal use according to the present invention in male human patients.
Particularly preferred 3,7-diazabicyclo[3,3,1]nonane compounds are the 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compound tedisamil and the physiologically compatible acid addition salts and/or solvates thereof, these are most preferably used as compounds for the production of pharmaceutical preparations for the treatment and/or prophylaxis of of antiarrhythmic male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients. If a tedisamil acid addition salt is used, it may preferably be used according to the invention in the form of tedisamil hydrochloride or in the form of tedisamil sesquifumarate for the treatment of male human patients. Further pharmacologic-ally compatible acid addition salts of tedisamil are known from European Patent No.
EP
103,833. Thus, salts with inorganic acids, e.g. sulfuric acid or hydrohalic acids, especially hydrochloric acid; or with organic acids, for instance lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid, tartaric acid, lactic acid, malefic acid, citric acid or salicylic acid; or with sulfonic acids, for instance lower alkyl sulfonic acids such as methane sulfonic acid, or benzene sulfonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluene sulfonic acid, are suitable as physiologically acceptable acid addition salts of the compounds of Formula I.
Surprisingly, it has been found that the 3,7,9, 9-tetra-substituted 3,7-diazabicyclo[3,3,1]nonane compounds corresponding to Formula I are distinguished by superior effects in anti-arrhythmic male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients, in addition to the aforementioned already known general heart-affecting properties. The superior anti-arrhythmic effect of the compounds of Formula I
in male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients, can be demonstrated by clinical test data with human patients which prove the surprising suitability of 3,7-diazabicyclo[3,3,1]nonane compounds, e.g. of tedisamil and its acid addition salts, for the treatment and/or prophylaxis of anti-arrhythmic effects in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
DESGRIPTION OF CLINICAL STUDY DESIGN AND RESULTS
A) Phase II Clinical Study in Humans The analysis of a first study in humans showed surprisingly that there is a gender difference related to efficacy, e.g. that male human patients show a higher conversion rate compared to women when treated with tedisamil. Furthermore, the male human patients show less safety issues than female human patients. Hence, it was surprisingly found that tedisamil as compared to female human patients shows specificity for male human patients in anti-arrhythmic treatment, and in particular in conversion of recent onset of atrial fibrillation (Afib) to normal sinus rhythm (NSR).
This first clinical study in humans was a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Sequential Ascending Dose Groups Study to evaluate the Efficacy and Safety of Intravenous Tedisamil in the Rapid Conversion to Normal Sinus Rhythm in Patients with Atrial Fibrillation or Flutter. The active ingredient used was tedisamil dihydrochloride. The study was designed as a phase II study and executed in 35 to 40 centers in 3 to 4 countries. Study duration: Screening: up to 48 hours;
treatment (in-patient): single 30-minute infusion; safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
The primary efficacy objective of the study was to demonstrate the superiority of any dose of tedisamil to placebo in the termination of atrial fibrillation/flutter as measured by the percentage of human patients converted to normal sinus rhythm (NSR) (for at least 60 seconds) at any time within 2.5 hours after the start of infusion, in humans.
Secondary efficacy objectives were to determine the percentage of human patients remaining in sinus rhythm at 2.5 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the percentage of human patients remaining in sinus rhythm at 24 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the time to conversion after the start of the infusion of tedisamil versus placebo; and to determine the dose- and plasma concentration-response relationships of tedisamil versus placebo. Safety objective: determining the safety and tolerability of tedisamil versus placebo.
The following methodology for the study in humans was applied: A multi-center, double-blind, randomized, placebo-controlled, sequential ascending dose groups study to evaluate the efficacy and safety of intravenous tedisamil versus placebo.
The study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes The first patient group received 0.4 mg/kg bodyweight (bw), infused as 0.2 mg/kg bw within 10 minutes, continued with 0.2 mg/kg bw infused within 20 minutes. The next higher dose 0.6 mg/kg bw (0.3 mg/kg bw infused within 10 min, continued with 0.3 mg/kg bw infused within 20 minutes) was only administered after the initial dose has been assessed (blinded) and found to be safe. A
third stage may be added with a higher dose. Tedisamil blood concentrations were assessed during the infusion (at 10 and 30 minutes), at conversion to normal sinus rhythm, at recurrence and 24 hours after start of infusion.
Planned number of human subjects: 330 randomized (110 patients per dose group) Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 48 hours, occurring as a first or recurrent episode.
Test Product, Dose and Mode of Administration:
~ Tedisamil (0.4 mg/kg body weight) ~ Tedisamil (0.6 mg/kg body weight) Both dosages were given as an intravenous regimen.
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 ) Efficacy:
Primary efficacy: the percentage of human patients converted to normal sinus rhythm (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug.
Secondary efficacy: percentage of human patients in NSR at 2.5 and 24 hours after start of infusion; time to conversion; dose- and concentration-response relationships.
2 Safet Physical examination, ECG, 24-hour Holter monitoring, vital signs, laboratory evaluations and adverse events.
Statistical Methods:
All efficacy variables were evaluated separately for human patients with atria) fibrillation and human patients with atria) flutter. Percentages of conversion were compared among treatment groups using a logistic regression model with factors for treatment group and center. Times to conversion were compared among treatment groups using a Cox proportional hazards model with factors for treatment group and center. Dose-response and concentration-response relationships were examined using descriptive statistics.
For the calculation of the number of human patients the following assumptions were made:
1. For atria) fibrillation patients, the percentage of conversion to normal sinus rhythm (at any time within 2.5 hours after the initiation of the infusion) in the placebo group is equal to 20% and the clinically relevant difference is 20%.
2. For atria) flutter patients, the percentage of conversion to normal sinus rhythm in the placebo group is equal to 10% and the clinically relevant difference is 40%.
Interim analyses for efficacy was performed halfway the first and second stages by an external statistician. The purpose is to terminate a stage when the tedisamil dose used in that stage is inefficacious. Technically, each interim analysis was a predictive power calculation for the comparison of tedisamil and placebo with respect to the primary efficacy variable. Blinded safety reviews were performed at the same time as the efficacy analyses and, in addition, at the end of the each stage (if applicable).
B) Phase III Clinical Study in Humans The analysis of a second study in humans confirmed the finding of the first study, e.g. that there is a gender difference related to efficacy, e.g. that male human patients show a higher conversion rate compared to women when treated with tedisamil.
This second clinical study in humans was a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Design Study to evaluate the Efficacy and Safety of Intravenous Tedisamil Sesquifumarate in the Rapid Conversion to Normal Sinus Rhythm in Subjects with Recent Onset Atrial Fibrillation or Flutter.
The active ingredient used was tedisamil sesqifumarate. The study was designed as a phase II study and executed in 30 to 40 centers in 5 countries. Study duration:
Screening: up to 48 hours; treatment (in-patient): single 30-minute infusion;
safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
The primary efficacy objective of the study in humans was to demonstrate the superiority of any dose oftedisamil sesquifumarate to placebo in the rapid conversion to normal sinus rhythm (for at least 60 seconds), as measured by the percentage of subjects converted at any time within 2.5 hours after the start of infusion.
Secondary efficacy objectives were to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 2.5 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 24 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of human subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at hospital discharge; to determine the time to conversion to normal sinus rhythm after the start of the infusion of tedisamil sesquifumarate versus placebo; to determine the dose- and concentration-response relationships of tedisamil sesquifumarate versus placebo; and to determine the energy required for DC cardioversion of tedisamil sesquifumarate versus placebo.
Safety l0 objective: determining the safety and tolerability of tedisamil sesquifumarate versus placebo.
The following methodology was applied: A multi-center, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of intravenous tedisamil sesquifumarate versus placebo. The study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes.
Subjects were randomly assigned to receive either:
- 0.32 mg tedisamil free base per kg bodyweight (bw) (0.16 mg/kg bw within 10 minutes, followed by 0.16 mg/kg bw within 20 minutes); or - 0.48 mg tedisamil free base per kg bw (0.24 mglkg bw within 10 min, followed by 0.24 mg/kg bw within 20 minutes); or - 0.64 mg tedisamil free base per kg bw (0.32 mg/kg bw within 10 min, followed by 0.32 mg/kg bw within 20 minutes); or - a 30 minute placebo infusion.
Planned number of human subj e~ cts:
212 randomized atrial fibrillation subjects (53 human subjects per treatment group).
These subjects are the primary target population. In addition, 80 {20 per treatment group) subjects with atrial flutter considered to be enrolled within the scope of this study.
However, the study could be terminated without all atrial flutter subjects enrolled if the planned number of atrial fibrillation subjects has been reached.
Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 45 days, occurring as a first or recurrent episode.
Test Product, Dose and Mode of Administration:
Test Product, Dose and Mode of Administration:
- Tedisamil free base 0.32 mg/kg body weight (equivalent to 0.51 mg/kg tedisamil sesquifumarate and to 0.4 mg/kg tedisamil dihydrochloride - Tedisamil free base 0.48 mg/kg body weight (equivalent to 0.77 mg/kg tedisamil sesquifumarate and to 0.6 mglkg tedisamil dihydrochloride - Tedisamil free base 0.64 mg/kg body weight (equivalent to 1.02 mg/kg tedisamil sesquifumarate and to 0.8 mg/kg tedisamil dihydrochloride The dosages will be given as an intravenous regimen.
Tedisamil doses in the protocol refer to tedisamil free base.
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion similar to tedisamil infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 Efficac Primary efficacy: the percentage of human subjects converted to normal sinus rhythm (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug.
Secondary efficacy: percentage of human subjects in normal sinus rhythm at any time within 2.5 hours and at 24 hours after start of infusion, as well as at hospital discharge, time to conversion, dose- and concentration-response relationships and DC
cardioversion energy.
2 Safet Physical examination, ECG, 24-hour Hotter monitoring, vital signs, laboratory evaluations and adverse events.
Statistical Methods:
Percentages of conversion will be compared among treatment groups using the (Pearson) chi-square statistics. Times to conversion will be compared among treatment groups using the log-rank test. Dose-response and concentration-response relationships and the energy required for DC conversion will be examined using descriptive statistics.
Subjects with atrial fibrillation and atrial flutter will be separately analyzed. In addition, both populations will be pooled for analysis. All analyses involving the atrial flutter subject population will be considered as exploratory.
Table I: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Ant~arrhythrnic Tre~tnient inritt Gender: TecC~sa~milv plabebo Q4mgk ~ , ( iaman f. 9 6 m~lk~
. . ~...) .. ........ ... . ... . .. ..
. . . ~.... .. . .
.
Atrial FibrillationMale 18135 (51.4 18 / 26 (69.2 2 / 24 (8.3 %) %) %) Female 6 / 17 35.3 6 / 16 37.5 2 / 22 9.1 % %
Atrial FlutterMale 1 / 7 (14.3 1 / 5 (20.0 O / 10 %) %) Female 0 / 2 2 I 6 33.3 0 / 3 %
Overall Male 19 / 42 (45.219 / 31 (61.3 2 / 34 (5.9 %) %) %) -Female 6 /19 (31.6 8 / 22 (36.4 2 / 25 (8.0 ~ %) % ) %) Table II: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
Human patients with atrial fibrillation ITT human patient sample; human patients with DC cardioversion are excluded.
Antiarrhythmic Gende r i. . Treatment (Humans) Age , with Male Tedisamil placebo < 65 rs 0.4 mglkg 0,~
~glkg 10 ! 20 (50.0 %) 13 / 18 (72.2 %) 1 ! 14 (7.1 %) >=65yrs 8/15(51.4%) 518(62.5%) 1/10(10%) Total 18 / 35 (51.4 18 l 26 (69.22 / 24 (8.3 %) %) %) Female < 65 yrs 2 ! 5 (40.0 1 / 3 (33.3 1 / 5 (20.0 %) %) %) > = 65 4 / 12 (33.3 5 / 13 (38.5 1 / 17 (5.9 yrs %) %) %) Total 6 /17 (35.3 6 /16 (37.5 2122 (9.1 %) %) %) Table III: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Antiar~hythryicI'reatinentvuith Ge~ider. ',1'ec t~~ai~it Placebo ..
(~uxnans)a 4 nig/kg _ .~ 6 rri , . , : .
, ! ~
g ~.
Atrial FibrillationMale 18/ 35 (51.418 I 26 (69.22 I24 (8.3 %) %) %) p-value, ChiSq < 0.001 < 0.001 (vs lacebo Female 6 / 17 (35.36 / 16 (37.5 2 / 22 (9.1 %) %) %) p-value, ChiSq < 0.045 < 0.034 (vs lacebo Atrial FlutterMale 1 17 (14.3 1 / 5 (20.0 0 / 10 %) %) p-value, ChiSq 0.218 0.143 (vs lacebo Female 0 / 2 2 / 6 (33.3 0 / 3 %) p-value, ChiSq -- 0.257 (vs lacebo Overall Male 19 / 42 (45.219 / 31 (61.32 / 34 (5.9 %) %} %) p-value, ChiSq < 0.001 < 0.001 (vs lacebo Female 6 /19 {31.6 8 l 22 (36.4 2 / 25 (8.0 %) %) p-value, ChiSq < 0.045 < 0.018 (vs lacebo It can be seen from these data that the anti-arrhythmic male human patients respond to the treatment with tedisamil more specifically than female human patients in the anti-arrhythmic treatment, and in particular in the conversion of recent onset of atrial fibrillation (Afib)Iflutter to normal sinus rhythm (NSR).
What is particularly surprising is the effectiveness of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates in male human patients, as proved by the above results of the studies in humans, in the treatment and/or prophylaxis of anti-an-hythmic events in male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) to NSR in male human patients, since such human gender difference related to efficacy has never been observed before in a vast variety of investigations with tedisamil in both human genders, and in particular this gender specificity has neither been observed in pre-clinical animal studies, as described in the state of the art.
From the results regarding efficacy of tedisamil found in the studies with human patients it may be summarized thattedisamil-like 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil itself, as well as the acid addition salts, show higher conversion rates in male human patients as compared to female human patients. Extension of infusion beyond the times indicated above did not produce higher conversion rates. From the results it may be summarized regarding safety: Almost all observed TdP
(Torsade de Point) in 30 min regimen were in female human patients. Only one male human patient showed TdP with high dosage on 0.72 in 3114 study.
As a therapeutic agent, 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates, may be contained according to the invention, together with conventional pharmaceutical auxiliaries andlor carriers, in solid or liquid pharmaceutical preparations dedicated to the administration in humans. Examples of solid preparations are preparations which can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or alternatively suppositories. These preparations may contain conventional pharmaceutical inorganic and/or organic carriers, such as talcum, lactose or starch, in addition to conventional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents. Liquid preparations such as suspensions or emulsions of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates thereof, may contain the usual diluents such as water, oils and/or suspension agents such as polyethylene glycols and the like. Other auxiliaries may additionally be added, such as preservatives, taste correctives and the like.
The 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can be mixed and formulated with the pharmaceutical auxiliaries and/or carriers in known manner. For the production of solid medicament forms dedicated to human beings, 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can for example be mixed with the auxiliaries and/or carriers in conventional manner and can be wet or dry granulated. The granules or powder can be poured directly into capsules or be pressed into tablet cores in conventional manner. These can be coated in known manner if desired.
EXAMPLES
The following Examples 1 to 3 describe pharmaceutical preparations according to the invention which contain an active substance of Formula I, and also the production of such pharmaceutical preparations. The following examples explain the production of pharmaceutical preparations containing tedisamil dihydrochloride.
Pharmaceutical preparations containing tedisamil sesquifumarate may be obtained in an analogous manner.
Example 1: Tablets Composition:
parts of N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-diazabicyclo[3,3,1]-nonane dihydrochloride parts of corn starch 55 parts of lactose 5 parts of polyvinylpyrrolidone 2 parts of magnesium stearate 3 parts of talcum Total 115 parts PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, additional deionized water was added. The moist granules were passed through a 2 mm sieve, dried on trays at 40 DEG C. and then passed through a 1 mm sieve (Frewitt machine). After the granules had been mixed with magnesium stearate and talcum, tablets weighing 115 mg were pressed therefrom, so that each tablet contained 20 mg of the active substance.
Example 2: Capsules Composition 20 parts of N-isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3,1]nonane dihydrogen fumarate 20 parts of corn starch 45 parts of lactose 3 parts of polyvinylpyrrolidone 1.5 partsof magnesium stearate 0.5 partsof highly dispersed silicic acid Total 90 parts PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, deionized water was added. The moist granules were passed through a 1.6 mm sieve (Frewitt machine), dried on trays at 40 DEG C., and then passed through a 1 mm sieve (Frewitt). After the granules had been mixed with magnesium stearate and highly dispersed silicic acid ("Aerosil 200", from Degussa), 90 mg thereof in each case were filled by means of an automatic encapsulating machine into size 4 hard gelatin capsules, so that each capsule contained 20 mg of active substance.
Example 3: Ampoules Composition (per ampoule) mg N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane dihydrochloride 16 mg Sodium chloride Water for injection purposes to make up to 2.0 ml PREPARATION METHOD
Sodium chloride was dissolved in water for injection purposes. The active substance was added and dissolved while stirring. Sufficient water for injection purposes was added to make up the final volume. The mixture was passed through a 0.25 µ membrane filter.
2.15 ml aliquots were filled into brown glass ampoules, and the ampoules were hermetically closed. The ampoules were sterilized with steam for 30 minutes at C. 2 ml of the resulting injection solution contains 5 mg of the active substance.
Another object of the invention is to provide new anti-arrhythmic pharmaceutical compositions having an improved activity profile for the use in male human patients.
The objects of the invention are achieved by surprisingly discovering that 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates of said compounds are particularly suitable for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients. According to a further aspect of the invention, the objects are achieved by providing an anti-arrhythmic pharmaceutical composition comprising an anti-arrhythmic amount effective in male human patients of at least one anti-arrhythmic active 3,7-diaza-bicyclo[3,3,1]nonane compound as described in the present invention.
The subject of the invention is therefore the use of the use of 3,7-diaza-bicyclo[3,3,1]nonane compounds, its physiologically acceptable acid addition salts and/or solvates thereof for the production of a pharmaceutical preparation for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
The compounds suitable for this novel medicinal use in male human patients are 3,7-diazabicyclo[3,3,1]nonane compounds corresponding to the Formula I:
I
R1 ~N N~R4 wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, or a benzyl group, R2 represents a lower alkyl group, and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms, and R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, a group corresponding to the Formula a:
/ /~ a z wherein R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and Z represents an alkylene chain containing from 1 to 3 carbon atoms or a propenylene chain having a double bond which is conjugated with the phenyl group, or a group corresponding to the Formula b:
\ R6 a CH
a R7 wherein R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy, or a physiologically acceptable acid addition salt andlor solvate thereof.
Particularly suited compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula I, wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms. In further preferred compounds of Formula I the substituent R4 represents an alkyl group containing from 1 to 6 carbon atoms, a cycloalkylalkyl group containing from 4 to 7 carbon atoms, or a group corresponding to Formula b.
Preferred compounds for the novel medicinal use in male human patients according to the invention are compounds of Formula 1, wherein R1 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms, and R4 represents an alkyl group containing from 3 to fi carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms. Said 3,7-diazabicyclo-[3,3,1]nonane compound may be a 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compound of Formula I wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another each denote a straight-chain or branched alkyl group of 3-4 carbon atoms or the cyclopropylmethyl group, and physiologically acceptable acid addition salts andlor solvates thereof.
Preferred salts for this group of compounds are fumaric acid salts of 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compounds containing 1.5 moles of fumaric acid per mole of compound of formula I.
Further preferred compounds for the novel medicinal use in male human patients according to the invention are compounds selected from the group consisting of N,N'-dicyclopropyl-methyl-9, 9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane {tedisamil), N-isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3,1]nonane, and physiologically acceptable acid addition salts and/or solvates thereof.
Preferred salts for this group of compounds are fumaric acid salts of N,N'-dicyclopropylmethyl-9, tetramethylene-3,7-diazabicyclo[3,3,1]nonane (tedisamil) or of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo[3,3,1]nonane containing 1.5 moles of fumaric acid per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound.
Alternatively, as acid addition salts of the 3,7-diazabicyclo[3,3,1]nonane compounds the hydrochloride salts are also very suitable for the novel medicinal use according to the present invention in male human patients.
Particularly preferred 3,7-diazabicyclo[3,3,1]nonane compounds are the 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compound tedisamil and the physiologically compatible acid addition salts and/or solvates thereof, these are most preferably used as compounds for the production of pharmaceutical preparations for the treatment and/or prophylaxis of of antiarrhythmic male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients. If a tedisamil acid addition salt is used, it may preferably be used according to the invention in the form of tedisamil hydrochloride or in the form of tedisamil sesquifumarate for the treatment of male human patients. Further pharmacologic-ally compatible acid addition salts of tedisamil are known from European Patent No.
EP
103,833. Thus, salts with inorganic acids, e.g. sulfuric acid or hydrohalic acids, especially hydrochloric acid; or with organic acids, for instance lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid, tartaric acid, lactic acid, malefic acid, citric acid or salicylic acid; or with sulfonic acids, for instance lower alkyl sulfonic acids such as methane sulfonic acid, or benzene sulfonic acids optionally substituted in the benzene ring by halogen or lower alkyl, such as p-toluene sulfonic acid, are suitable as physiologically acceptable acid addition salts of the compounds of Formula I.
Surprisingly, it has been found that the 3,7,9, 9-tetra-substituted 3,7-diazabicyclo[3,3,1]nonane compounds corresponding to Formula I are distinguished by superior effects in anti-arrhythmic male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients, in addition to the aforementioned already known general heart-affecting properties. The superior anti-arrhythmic effect of the compounds of Formula I
in male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients, can be demonstrated by clinical test data with human patients which prove the surprising suitability of 3,7-diazabicyclo[3,3,1]nonane compounds, e.g. of tedisamil and its acid addition salts, for the treatment and/or prophylaxis of anti-arrhythmic effects in male human patients, preferably for conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
DESGRIPTION OF CLINICAL STUDY DESIGN AND RESULTS
A) Phase II Clinical Study in Humans The analysis of a first study in humans showed surprisingly that there is a gender difference related to efficacy, e.g. that male human patients show a higher conversion rate compared to women when treated with tedisamil. Furthermore, the male human patients show less safety issues than female human patients. Hence, it was surprisingly found that tedisamil as compared to female human patients shows specificity for male human patients in anti-arrhythmic treatment, and in particular in conversion of recent onset of atrial fibrillation (Afib) to normal sinus rhythm (NSR).
This first clinical study in humans was a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Sequential Ascending Dose Groups Study to evaluate the Efficacy and Safety of Intravenous Tedisamil in the Rapid Conversion to Normal Sinus Rhythm in Patients with Atrial Fibrillation or Flutter. The active ingredient used was tedisamil dihydrochloride. The study was designed as a phase II study and executed in 35 to 40 centers in 3 to 4 countries. Study duration: Screening: up to 48 hours;
treatment (in-patient): single 30-minute infusion; safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
The primary efficacy objective of the study was to demonstrate the superiority of any dose of tedisamil to placebo in the termination of atrial fibrillation/flutter as measured by the percentage of human patients converted to normal sinus rhythm (NSR) (for at least 60 seconds) at any time within 2.5 hours after the start of infusion, in humans.
Secondary efficacy objectives were to determine the percentage of human patients remaining in sinus rhythm at 2.5 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the percentage of human patients remaining in sinus rhythm at 24 hours after initiation of the intravenous infusion of tedisamil versus placebo; to determine the time to conversion after the start of the infusion of tedisamil versus placebo; and to determine the dose- and plasma concentration-response relationships of tedisamil versus placebo. Safety objective: determining the safety and tolerability of tedisamil versus placebo.
The following methodology for the study in humans was applied: A multi-center, double-blind, randomized, placebo-controlled, sequential ascending dose groups study to evaluate the efficacy and safety of intravenous tedisamil versus placebo.
The study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes The first patient group received 0.4 mg/kg bodyweight (bw), infused as 0.2 mg/kg bw within 10 minutes, continued with 0.2 mg/kg bw infused within 20 minutes. The next higher dose 0.6 mg/kg bw (0.3 mg/kg bw infused within 10 min, continued with 0.3 mg/kg bw infused within 20 minutes) was only administered after the initial dose has been assessed (blinded) and found to be safe. A
third stage may be added with a higher dose. Tedisamil blood concentrations were assessed during the infusion (at 10 and 30 minutes), at conversion to normal sinus rhythm, at recurrence and 24 hours after start of infusion.
Planned number of human subjects: 330 randomized (110 patients per dose group) Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 48 hours, occurring as a first or recurrent episode.
Test Product, Dose and Mode of Administration:
~ Tedisamil (0.4 mg/kg body weight) ~ Tedisamil (0.6 mg/kg body weight) Both dosages were given as an intravenous regimen.
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 ) Efficacy:
Primary efficacy: the percentage of human patients converted to normal sinus rhythm (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug.
Secondary efficacy: percentage of human patients in NSR at 2.5 and 24 hours after start of infusion; time to conversion; dose- and concentration-response relationships.
2 Safet Physical examination, ECG, 24-hour Holter monitoring, vital signs, laboratory evaluations and adverse events.
Statistical Methods:
All efficacy variables were evaluated separately for human patients with atria) fibrillation and human patients with atria) flutter. Percentages of conversion were compared among treatment groups using a logistic regression model with factors for treatment group and center. Times to conversion were compared among treatment groups using a Cox proportional hazards model with factors for treatment group and center. Dose-response and concentration-response relationships were examined using descriptive statistics.
For the calculation of the number of human patients the following assumptions were made:
1. For atria) fibrillation patients, the percentage of conversion to normal sinus rhythm (at any time within 2.5 hours after the initiation of the infusion) in the placebo group is equal to 20% and the clinically relevant difference is 20%.
2. For atria) flutter patients, the percentage of conversion to normal sinus rhythm in the placebo group is equal to 10% and the clinically relevant difference is 40%.
Interim analyses for efficacy was performed halfway the first and second stages by an external statistician. The purpose is to terminate a stage when the tedisamil dose used in that stage is inefficacious. Technically, each interim analysis was a predictive power calculation for the comparison of tedisamil and placebo with respect to the primary efficacy variable. Blinded safety reviews were performed at the same time as the efficacy analyses and, in addition, at the end of the each stage (if applicable).
B) Phase III Clinical Study in Humans The analysis of a second study in humans confirmed the finding of the first study, e.g. that there is a gender difference related to efficacy, e.g. that male human patients show a higher conversion rate compared to women when treated with tedisamil.
This second clinical study in humans was a Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Design Study to evaluate the Efficacy and Safety of Intravenous Tedisamil Sesquifumarate in the Rapid Conversion to Normal Sinus Rhythm in Subjects with Recent Onset Atrial Fibrillation or Flutter.
The active ingredient used was tedisamil sesqifumarate. The study was designed as a phase II study and executed in 30 to 40 centers in 5 countries. Study duration:
Screening: up to 48 hours; treatment (in-patient): single 30-minute infusion;
safety follow up: 24 hours (in-patient) with continuous telemetry and 28 day safety follow up.
The primary efficacy objective of the study in humans was to demonstrate the superiority of any dose oftedisamil sesquifumarate to placebo in the rapid conversion to normal sinus rhythm (for at least 60 seconds), as measured by the percentage of subjects converted at any time within 2.5 hours after the start of infusion.
Secondary efficacy objectives were to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 2.5 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at 24 hours after initiation of the infusion of tedisamil sesquifumarate versus placebo; to determine the percentage of human subjects converting to normal sinus rhythm at any time within 2.5 hours after start of the intravenous infusion and in normal sinus rhythm at hospital discharge; to determine the time to conversion to normal sinus rhythm after the start of the infusion of tedisamil sesquifumarate versus placebo; to determine the dose- and concentration-response relationships of tedisamil sesquifumarate versus placebo; and to determine the energy required for DC cardioversion of tedisamil sesquifumarate versus placebo.
Safety l0 objective: determining the safety and tolerability of tedisamil sesquifumarate versus placebo.
The following methodology was applied: A multi-center, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of intravenous tedisamil sesquifumarate versus placebo. The study drug was infused over 30 minutes, receiving half the dose within 10 minutes and half the dose within the remaining 20 minutes.
Subjects were randomly assigned to receive either:
- 0.32 mg tedisamil free base per kg bodyweight (bw) (0.16 mg/kg bw within 10 minutes, followed by 0.16 mg/kg bw within 20 minutes); or - 0.48 mg tedisamil free base per kg bw (0.24 mglkg bw within 10 min, followed by 0.24 mg/kg bw within 20 minutes); or - 0.64 mg tedisamil free base per kg bw (0.32 mg/kg bw within 10 min, followed by 0.32 mg/kg bw within 20 minutes); or - a 30 minute placebo infusion.
Planned number of human subj e~ cts:
212 randomized atrial fibrillation subjects (53 human subjects per treatment group).
These subjects are the primary target population. In addition, 80 {20 per treatment group) subjects with atrial flutter considered to be enrolled within the scope of this study.
However, the study could be terminated without all atrial flutter subjects enrolled if the planned number of atrial fibrillation subjects has been reached.
Diagnosis and Main Criteria for Inclusion:
Atrial fibrillation or flutter with a duration of > 3 hours and < 45 days, occurring as a first or recurrent episode.
Test Product, Dose and Mode of Administration:
Test Product, Dose and Mode of Administration:
- Tedisamil free base 0.32 mg/kg body weight (equivalent to 0.51 mg/kg tedisamil sesquifumarate and to 0.4 mg/kg tedisamil dihydrochloride - Tedisamil free base 0.48 mg/kg body weight (equivalent to 0.77 mg/kg tedisamil sesquifumarate and to 0.6 mglkg tedisamil dihydrochloride - Tedisamil free base 0.64 mg/kg body weight (equivalent to 1.02 mg/kg tedisamil sesquifumarate and to 0.8 mg/kg tedisamil dihydrochloride The dosages will be given as an intravenous regimen.
Tedisamil doses in the protocol refer to tedisamil free base.
Reference Therapy, Dose and Mode of Administration:
Placebo (vehicle) administered as a 30-minute intravenous infusion similar to tedisamil infusion.
Duration of Treatment:
The total infusion time is 30 minutes, with half the dose infused within 10 minutes, and half the dose infused within the remaining 20 minutes.
Criteria for Evaluation:
1 Efficac Primary efficacy: the percentage of human subjects converted to normal sinus rhythm (for at least 60 seconds) at any time within 2.5 hours after the initiation of the infusion of study drug.
Secondary efficacy: percentage of human subjects in normal sinus rhythm at any time within 2.5 hours and at 24 hours after start of infusion, as well as at hospital discharge, time to conversion, dose- and concentration-response relationships and DC
cardioversion energy.
2 Safet Physical examination, ECG, 24-hour Hotter monitoring, vital signs, laboratory evaluations and adverse events.
Statistical Methods:
Percentages of conversion will be compared among treatment groups using the (Pearson) chi-square statistics. Times to conversion will be compared among treatment groups using the log-rank test. Dose-response and concentration-response relationships and the energy required for DC conversion will be examined using descriptive statistics.
Subjects with atrial fibrillation and atrial flutter will be separately analyzed. In addition, both populations will be pooled for analysis. All analyses involving the atrial flutter subject population will be considered as exploratory.
Table I: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Ant~arrhythrnic Tre~tnient inritt Gender: TecC~sa~milv plabebo Q4mgk ~ , ( iaman f. 9 6 m~lk~
. . ~...) .. ........ ... . ... . .. ..
. . . ~.... .. . .
.
Atrial FibrillationMale 18135 (51.4 18 / 26 (69.2 2 / 24 (8.3 %) %) %) Female 6 / 17 35.3 6 / 16 37.5 2 / 22 9.1 % %
Atrial FlutterMale 1 / 7 (14.3 1 / 5 (20.0 O / 10 %) %) Female 0 / 2 2 I 6 33.3 0 / 3 %
Overall Male 19 / 42 (45.219 / 31 (61.3 2 / 34 (5.9 %) %) %) -Female 6 /19 (31.6 8 / 22 (36.4 2 / 25 (8.0 ~ %) % ) %) Table II: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
Human patients with atrial fibrillation ITT human patient sample; human patients with DC cardioversion are excluded.
Antiarrhythmic Gende r i. . Treatment (Humans) Age , with Male Tedisamil placebo < 65 rs 0.4 mglkg 0,~
~glkg 10 ! 20 (50.0 %) 13 / 18 (72.2 %) 1 ! 14 (7.1 %) >=65yrs 8/15(51.4%) 518(62.5%) 1/10(10%) Total 18 / 35 (51.4 18 l 26 (69.22 / 24 (8.3 %) %) %) Female < 65 yrs 2 ! 5 (40.0 1 / 3 (33.3 1 / 5 (20.0 %) %) %) > = 65 4 / 12 (33.3 5 / 13 (38.5 1 / 17 (5.9 yrs %) %) %) Total 6 /17 (35.3 6 /16 (37.5 2122 (9.1 %) %) %) Table III: Conversion of recent onset of atrial fibrillation (Afib) to NSR
Conversion to NSR at any time within 2.5 hrs after start of infusion.
ITT human patient sample; human patients with DC cardioversion are excluded.
Antiar~hythryicI'reatinentvuith Ge~ider. ',1'ec t~~ai~it Placebo ..
(~uxnans)a 4 nig/kg _ .~ 6 rri , . , : .
, ! ~
g ~.
Atrial FibrillationMale 18/ 35 (51.418 I 26 (69.22 I24 (8.3 %) %) %) p-value, ChiSq < 0.001 < 0.001 (vs lacebo Female 6 / 17 (35.36 / 16 (37.5 2 / 22 (9.1 %) %) %) p-value, ChiSq < 0.045 < 0.034 (vs lacebo Atrial FlutterMale 1 17 (14.3 1 / 5 (20.0 0 / 10 %) %) p-value, ChiSq 0.218 0.143 (vs lacebo Female 0 / 2 2 / 6 (33.3 0 / 3 %) p-value, ChiSq -- 0.257 (vs lacebo Overall Male 19 / 42 (45.219 / 31 (61.32 / 34 (5.9 %) %} %) p-value, ChiSq < 0.001 < 0.001 (vs lacebo Female 6 /19 {31.6 8 l 22 (36.4 2 / 25 (8.0 %) %) p-value, ChiSq < 0.045 < 0.018 (vs lacebo It can be seen from these data that the anti-arrhythmic male human patients respond to the treatment with tedisamil more specifically than female human patients in the anti-arrhythmic treatment, and in particular in the conversion of recent onset of atrial fibrillation (Afib)Iflutter to normal sinus rhythm (NSR).
What is particularly surprising is the effectiveness of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates in male human patients, as proved by the above results of the studies in humans, in the treatment and/or prophylaxis of anti-an-hythmic events in male human patients, in particular in the conversion of recent onset of atrial fibrillation (Afib) to NSR in male human patients, since such human gender difference related to efficacy has never been observed before in a vast variety of investigations with tedisamil in both human genders, and in particular this gender specificity has neither been observed in pre-clinical animal studies, as described in the state of the art.
From the results regarding efficacy of tedisamil found in the studies with human patients it may be summarized thattedisamil-like 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil itself, as well as the acid addition salts, show higher conversion rates in male human patients as compared to female human patients. Extension of infusion beyond the times indicated above did not produce higher conversion rates. From the results it may be summarized regarding safety: Almost all observed TdP
(Torsade de Point) in 30 min regimen were in female human patients. Only one male human patient showed TdP with high dosage on 0.72 in 3114 study.
As a therapeutic agent, 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates, may be contained according to the invention, together with conventional pharmaceutical auxiliaries andlor carriers, in solid or liquid pharmaceutical preparations dedicated to the administration in humans. Examples of solid preparations are preparations which can be administered orally, such as tablets, coated tablets, capsules, powders or granules, or alternatively suppositories. These preparations may contain conventional pharmaceutical inorganic and/or organic carriers, such as talcum, lactose or starch, in addition to conventional pharmaceutical auxiliaries, for example lubricants or tablet disintegrating agents. Liquid preparations such as suspensions or emulsions of 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably of tedisamil, and of pharmaceutically acceptable acid addition salts and/or solvates thereof, may contain the usual diluents such as water, oils and/or suspension agents such as polyethylene glycols and the like. Other auxiliaries may additionally be added, such as preservatives, taste correctives and the like.
The 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can be mixed and formulated with the pharmaceutical auxiliaries and/or carriers in known manner. For the production of solid medicament forms dedicated to human beings, 3,7-diazabicyclo-[3,3,1]nonane compounds, preferably of 9,9-alkylene-3,7-diazabicyclo[3,3,1]-nonane compounds, and most preferably tedisamil, and pharmaceutically acceptable acid addition salts and/or solvates thereof, can for example be mixed with the auxiliaries and/or carriers in conventional manner and can be wet or dry granulated. The granules or powder can be poured directly into capsules or be pressed into tablet cores in conventional manner. These can be coated in known manner if desired.
EXAMPLES
The following Examples 1 to 3 describe pharmaceutical preparations according to the invention which contain an active substance of Formula I, and also the production of such pharmaceutical preparations. The following examples explain the production of pharmaceutical preparations containing tedisamil dihydrochloride.
Pharmaceutical preparations containing tedisamil sesquifumarate may be obtained in an analogous manner.
Example 1: Tablets Composition:
parts of N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-diazabicyclo[3,3,1]-nonane dihydrochloride parts of corn starch 55 parts of lactose 5 parts of polyvinylpyrrolidone 2 parts of magnesium stearate 3 parts of talcum Total 115 parts PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, additional deionized water was added. The moist granules were passed through a 2 mm sieve, dried on trays at 40 DEG C. and then passed through a 1 mm sieve (Frewitt machine). After the granules had been mixed with magnesium stearate and talcum, tablets weighing 115 mg were pressed therefrom, so that each tablet contained 20 mg of the active substance.
Example 2: Capsules Composition 20 parts of N-isobutyl-N'-isopropyl-9,9-pentamethylen-3,7-diazabicyclo[3,3,1]nonane dihydrogen fumarate 20 parts of corn starch 45 parts of lactose 3 parts of polyvinylpyrrolidone 1.5 partsof magnesium stearate 0.5 partsof highly dispersed silicic acid Total 90 parts PREPARATION METHOD
The active substance was mixed with corn starch and finely powdered lactose in a mixer.
The resulting mixture was thoroughly moistened with a 20% solution of polyvinylpyrrolidone ("Kollidon 25", from BASF) in deionized water. If necessary, deionized water was added. The moist granules were passed through a 1.6 mm sieve (Frewitt machine), dried on trays at 40 DEG C., and then passed through a 1 mm sieve (Frewitt). After the granules had been mixed with magnesium stearate and highly dispersed silicic acid ("Aerosil 200", from Degussa), 90 mg thereof in each case were filled by means of an automatic encapsulating machine into size 4 hard gelatin capsules, so that each capsule contained 20 mg of active substance.
Example 3: Ampoules Composition (per ampoule) mg N,N'-dicyclopropylmethyl-9,9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane dihydrochloride 16 mg Sodium chloride Water for injection purposes to make up to 2.0 ml PREPARATION METHOD
Sodium chloride was dissolved in water for injection purposes. The active substance was added and dissolved while stirring. Sufficient water for injection purposes was added to make up the final volume. The mixture was passed through a 0.25 µ membrane filter.
2.15 ml aliquots were filled into brown glass ampoules, and the ampoules were hermetically closed. The ampoules were sterilized with steam for 30 minutes at C. 2 ml of the resulting injection solution contains 5 mg of the active substance.
Claims (10)
1. The use of 3,7-diazabicyclo[3,3,1]nonane compounds, its physiologically acceptable acid addition salts and/or solvates thereof for the production of a pharmaceutical preparation for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients, preferably in conversion of recent onset of atrial fibrillation (Afib) or flutter to normal sinus rhythm (NSR) in male human patients.
2. Use according to claim 1 wherein the 3,7-diazabicyclo[3,3,1]nonane compounds are corresponding to the Formula I:
wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, or a benzyl group, R2 represents a lower alkyl group, and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms, and R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, a group corresponding to the Formula a:
wherein R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and Z represents an alkylene chain containing from 1 to 3 carbon atoms or a propenylene chain having a double bond which is conjugated with the phenyl group, or a group corresponding to the Formula b:
wherein R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy, or a physiologically acceptable acid addition salt and/or solvate thereof.
wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms, an alkylene group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, or a benzyl group, R2 represents a lower alkyl group, and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain containing from 3 to 6 carbon atoms, and R4 represents an alkyl group containing from 1 to 6 carbon atoms, an alkenyl group containing from 3 to 6 carbon atoms having a double bond which is not linked directly to the nitrogen atom, a cycloalkylalkyl group containing from 4 to 9 carbon atoms, a group corresponding to the Formula a:
wherein R5 represents hydrogen, halogen, lower alkyl or lower alkoxy, and Z represents an alkylene chain containing from 1 to 3 carbon atoms or a propenylene chain having a double bond which is conjugated with the phenyl group, or a group corresponding to the Formula b:
wherein R6 represents hydrogen, halogen, lower alkyl or lower alkoxy, and R7 represents hydrogen, halogen, lower alkyl or lower alkoxy, or a physiologically acceptable acid addition salt and/or solvate thereof.
3. Use according to claim 1, wherein R1 represents an alkyl group containing from 1 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms.
4. Use according to claim 1, wherein R4 represents an alkyl group containing from 1 to 6 carbon atoms, a cycloalkylalkyl group containing from 4 to 7 carbon atoms, or a group corresponding to Formula b.
5. Use according to claim 1, wherein R1 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms, and R4 represents an alkyl group containing from 3 to 6 carbon atoms or a cycloalkylalkyl group containing from 4 to 7 carbon atoms.
6. Use according to claim 1, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is a 9,9-alkylene-3,7-diazabicyclo[3.3.1]nonane compound of Formula I
wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another each denote a straight-chain or branched alkyl group of 3-4 carbon atoms or the cyclopropylmethyl group, and physiologically acceptable acid addition salts and/or solvates thereof.
wherein R2 and R3 together form an alkylene chain containing from 4 to 5 carbon atoms, and R1 and R4 independently of one another each denote a straight-chain or branched alkyl group of 3-4 carbon atoms or the cyclopropylmethyl group, and physiologically acceptable acid addition salts and/or solvates thereof.
7. Use according to claim 6, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is a fumaric acid salt of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound containing 1.5 moles of fumaric acid per mole of compound of formula I.
8. Use according to claim 1, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is selected from the group consisting of N,N'-dicyclopropylmethyl-9,
9-tetramethylen-3,7-diazabicyclo[3,3,1]nonane, N-isobutyl-N'-isopropyl-9,9-pentamethylen-3, 7-diazabicyclo[3,3,1]nonane, and physiologically acceptable acid addition salts and/or solvates thereof.
9. Use according to claim 8, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is a fumaric acid salt of N,N'-dicyclopropylmethyl-9, 9-tetramethylene-3,7-diazabicyclo[3,3,1]nonane or of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3, diazabicyclo[3,3,1]nonane containing 1.5 moles of fumaric acid per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound.
9. Use according to claim 8, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is a fumaric acid salt of N,N'-dicyclopropylmethyl-9, 9-tetramethylene-3,7-diazabicyclo[3,3,1]nonane or of N-isobutyl-N'-isopropyl-9,9-pentamethylene-3, diazabicyclo[3,3,1]nonane containing 1.5 moles of fumaric acid per mole of said 9,9-alkylene-3,7-diazabicyclo[3.3.1]-nonane compound.
10. The use according to any of the Claims 1, 5 and 7, wherein said 3,7-diazabicyclo[3,3,1]nonane compound is a hydrochloride salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP03102243 | 2003-07-21 | ||
| EP03102243.7 | 2003-07-21 | ||
| PCT/EP2004/051532 WO2005011690A1 (en) | 2003-07-21 | 2004-07-19 | Use of 3,7-diazabicyclo`3, 3,1 !nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2533492A1 true CA2533492A1 (en) | 2005-02-10 |
Family
ID=34112472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002533492A Abandoned CA2533492A1 (en) | 2003-07-21 | 2004-07-19 | Use of 3,7-diazabicyclo[3,3,1]nonane compounds for the treatment and/or prophylaxis of anti-arrhythmic events in male human patients |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1648456A1 (en) |
| JP (1) | JP2006528155A (en) |
| CN (1) | CN1822833A (en) |
| AU (1) | AU2004260624A1 (en) |
| BR (1) | BRPI0412247A (en) |
| CA (1) | CA2533492A1 (en) |
| MX (1) | MXPA06000796A (en) |
| WO (1) | WO2005011690A1 (en) |
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| TWI510480B (en) | 2011-05-10 | 2015-12-01 | Gilead Sciences Inc | Fused heterocyclic compounds as ion channel modulators |
| TWI549944B (en) | 2011-07-01 | 2016-09-21 | 吉李德科學股份有限公司 | Fused heterocyclic compounds as ion channel modulators |
| NO3175985T3 (en) | 2011-07-01 | 2018-04-28 | ||
| WO2014134419A1 (en) * | 2013-03-01 | 2014-09-04 | Gilead Sciences, Inc. | Use of ikach blockers for the treatment of cardiac diseases |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3234697A1 (en) * | 1982-09-18 | 1984-03-22 | Kali-Chemie Pharma Gmbh, 3000 Hannover | NEW DIAZABICYCLO (3,3,1) NONANA |
| PT88381B (en) * | 1987-09-09 | 1995-07-06 | Kali Chemie Pharma Gmbh | PROCESS FOR THE PREPARATION OF NEW COMPOUNDS 3,7-DIAZABICYCLO (3,3,1) NONANO, AND OF PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
| DE4139763A1 (en) * | 1991-12-03 | 1993-06-09 | Kali-Chemie Pharma Gmbh, 3000 Hannover, De | CRYSTALLINE FUMAR ACID SALTS OF 9,9-ALKYLENE-3,7-DIAZABICYCLONONAN COMPOUNDS AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| TW200418468A (en) * | 2002-11-18 | 2004-10-01 | Solvay Pharm Gmbh | Liquid pharmaceutical formulations containing 3,7-diazabicyclo[3,3,1]nonane compounds and method of treatments relating to anti-arrhytmic events |
-
2004
- 2004-07-19 CN CNA200480019884XA patent/CN1822833A/en active Pending
- 2004-07-19 JP JP2006520832A patent/JP2006528155A/en not_active Withdrawn
- 2004-07-19 BR BRPI0412247-0A patent/BRPI0412247A/en not_active Application Discontinuation
- 2004-07-19 CA CA002533492A patent/CA2533492A1/en not_active Abandoned
- 2004-07-19 AU AU2004260624A patent/AU2004260624A1/en not_active Abandoned
- 2004-07-19 WO PCT/EP2004/051532 patent/WO2005011690A1/en not_active Application Discontinuation
- 2004-07-19 MX MXPA06000796A patent/MXPA06000796A/en not_active Application Discontinuation
- 2004-07-19 EP EP04742001A patent/EP1648456A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU2004260624A1 (en) | 2005-02-10 |
| JP2006528155A (en) | 2006-12-14 |
| WO2005011690A1 (en) | 2005-02-10 |
| MXPA06000796A (en) | 2006-04-07 |
| EP1648456A1 (en) | 2006-04-26 |
| BRPI0412247A (en) | 2006-09-19 |
| CN1822833A (en) | 2006-08-23 |
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